Comparative mouse skin tumorigenicity and induction of Ha-ras mutations by bay region diol epoxides of 5-methylchrysene and 5,6-dimethylchrysene.
We compared the tumor-initiating activities toward mouse skin of two structurally related polycyclic aromatic hydrocarbon diol epoxides: racemic anti-1,2,3,4-tetrahydro-5,6-dimethylchrysene-1,2-diol-3,4-epoxide (5,6-diMeCDE) and racemic anti-1,2,3,4-tetrahydro-5-methylchrysene-1,2-diol-3,4-epoxide (5-MeCDE). Tumors induced by these diol epoxides were analysed for mutations in the Ha-ras gene. 5,6-diMeCDE is derived from the non-planar parent compound 5,6-dimethylchrysene, and reacts to approximately equal extents with dA and dG in DNA, whereas 5-MeCDE is derived from a nearly planar parent compound, 5-methylchrysene, and reacts mainly with dG in DNA. 5,6-diMeCDE, at initiating doses of 33, 100 or 400 nmol per mouse, induced 1.2, 2.2 and 6.2 skin tumors per mouse, respectively. It was significantly less tumorigenic than 5-MeCDE which induced 3.1, 7.5 and 9.1 skin tumors per mouse at the same doses. Tumors induced by 5,6-diMeCDE had a large number of CAA-->CTA mutations in codon 61 of the Ha-ras gene: 50, 55 and 75% of the tumors analysed had this mutation at the 33, 100 and 400 nmol doses. No mutations were found in codons 12 and 13 in the tumors induced by 5,6-diMeCDE. In contrast, CAA-->CTA mutations in codon 61 were rarely seen in tumors induced by 5-MeCDE. At the highest dose of 5-MeCDE, 20% of the tumors analysed had mutations at G of codons 12 and 13. The results of this comparative study support the hypothesis that mutations in the Ha-ras gene in mouse skin tumors induced by PAH diol epoxides occur as a result of their direct reaction with the gene. However, pathways other than the commonly observed Ha-ras codon 61 mutations are clearly important in mouse skin tumorigenesis by these diol epoxides.
Hecht
S S
SS
University of Minnesota Cancer Center, Minneapolis 55455, USA.
Ronai
Z A
ZA
Dolan
L
L
Desai
D
D
Amin
S
S
D000818:Animals; D018383:Bay-Region, Polycyclic Aromatic Hydrocarbon; D002911:Chrysenes / Q000633:toxicity*; D005260:Female; D011905:Genes, ras / Q000187:drug effects*; D051379:Mice; D009153:Mutagens / Q000633:toxicity*; D016133:Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects / Q000473:pathology*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology; D013997:Time Factors
D002911:Chrysenes; D009153:Mutagens; C075956:1,2-dihydroxy-5,6-dimethyl-3,4-epoxy-1,2,3,4-tetrahydrochrysene; C037783:1,2-dihydroxy-epoxy-1,2,3,4-tetrahydro-5-methylchrysene